Evolution of Alachlor-Induced Nasal Neoplasms in the Long-Evans Rat

Genter, Mary Beth; Burman, Dawn M.; Dingeldein, Michael; Clough, Ian; Bolon, Brad

doi:10.1177/019262330002800602

Cited by 24 publications

(24 citation statements)

References 39 publications

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“…The results of the current study, together with previous work in the rat (Genter et al, 2000(Genter et al, , 2002a(Genter et al, , 2002b confirm that there is a marked species difference in response to alachlor between rats and mice. Rats treated chronically with alachlor (126 mg/kg/d) developed treatment-related olfactory tumors with ≥5 months of treatment.…”

Section: Discussionsupporting

confidence: 86%

“…These observations are in contrast to those previously reported in rat liver, which showed no enzyme induction (Wetmore et al, 1999). The distribution of CYP2A5 in the mouse nasal cavity is different from that previously reported for CYP2A3 in the rat (Genter et al, 2000). In the mouse, CYP2A5 immunoreactivity is most intense along the dorsal nasal septum and in the mucosa lining the dorsal medial meatus (Figure 3).…”

Section: Genter Et Alcontrasting

confidence: 88%

“…In the mouse, CYP2A5 immunoreactivity is most intense along the dorsal nasal septum and in the mucosa lining the dorsal medial meatus (Figure 3). The pattern of staining in rat nasal cavity sections (Figure 3) was identical (but weaker) to that seen with the anti-CYP2A10/2A11 antibody used in our previous studies (Genter et al, 2000). β-catenin immunoreactivity was undetectable in the olfactory mucosa of any of the mouse strains (as was the case with untreated rats (Genter et al, 2002b)), and did not change with alachlor treatment.…”

Section: Genter Et Alsupporting

confidence: 75%

“…Rats treated chronically with alachlor (126 mg/kg/d) developed treatment-related olfactory tumors with ≥5 months of treatment. The progression of these tumors to more malignant phenotypes was accompanied by cytoplasmic accumulation and nuclear localization of β-catenin, and an observation that is suggestive of activation of Wnt signaling (U.S. EPA, 1985;Genter et al, 2000Genter et al, , 2002aGenter et al, , 2002b. In contrast, in the present study, we found no neoplastic changes in any of the 3 strains examined (treated at a higher dose of 260 mg/kg/d).…”

Section: Discussioncontrasting

confidence: 61%

“…Alachlor-treated mice and the respective controls were sacrificed using carbon dioxide, and tissues were prepared as previously described (Genter et al, 2000). Nasal cavities were decalcified in 10% formic acid for approximately 5 days.…”

Section: Introductionmentioning

confidence: 99%

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Strain-Specific Effects of Alachlor on Murine Olfactory Mucosal Responses

2004

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Chloracetanilide herbicides are multisite carcinogens in rodents. Progression of alachlor-induced olfactory tumors in rats is accompanied by cytoplasmic accumulation and nuclear localization of β-catenin, suggesting activation of Wnt signaling. Female CD-1 mice were resistant to alachlorinduced olfactory carcinogenesis. The current studies were performed to determine whether Apc Min/+ mice, which have activated Wnt signaling due to mutation of the second allele of Apc, would be susceptible to alachlor olfactory carcinogenesis. Female and male Apc Min/+ mice, as well as Apc +/+ littermates received alachlor in the diet (260 mg/kg/d) for up to 3 months. Female A/J and C57BL/6J wild-type mice were also treated (for 10 and 14 months, respectively), as these strains vary in sensitivity to many respiratory tract insults. No olfactory mucosal tumors were observed in any of the mice, although alachlor-treated Apc Min/+ mice developed histological changes similar to those in alachlor-treated rats. Alachlor-treated A/J mice developed pronounced intracellular accumulation of amorphous eosinophilic material in the olfactory mucosa, foci of respiratory-like metaplasia, and hyperplasia of nasal mucus glands. A similar but less intense response was seen in C57BL/6J mice. Mice and rats had equivalent levels of the putative bioactivating enzyme (CYP2A) in olfactory mucosa, and mice had induced hepatic CYP3A and CYP2B enzymes with alachlor treatment, which may increase alachlor elimination. These studies extend previous observations by describing alachlor-induced olfactory mucosal changes in mice and suggest that hepatic metabolic enzyme induction may be responsible for resistance of mice to alachlor-induced olfactory carcinogenesis.

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Section: Discussionsupporting

confidence: 86%

Section: Genter Et Alcontrasting

confidence: 88%